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IMPACT OF THE HUMAN GENOME
PROJECT
Kennedy S. and Shuman C.
Division of Clinical & Metabolic Genetics, Hospital
for Sick Children and Department of Molecular
& Medical Genetics, University of Toronto, Canada
Abstract:
June 2000 heralded the first draft of the
human genome and with it a tremendous amount of
public attention to this monumental achievement.
Amidst the excitement regarding the potential
impact on clinical medicine and anticipating “the
development of rational strategies for minimizing
or preventing disease phenotypes altogether” (4)
there has also arisen concern about the ethical
use of this new technology as well as a healthy
dose of skepticism about its ultimate application
to clinical care(9). Clearly, as technology continues
to elucidate new genes and their function, both
in normal development and pathology, questions
and concerns about practical applications of this
information will continue to arise. The goal of
this article is to review the impact of the discoveries
of Human Genome Project (HGP) on the practice
of genetic counselling and clinical care as well
as to discuss the potential ethical dilemmas,
which may arise.
  History
of the Human Genome Project:
In 1988 funds were appropriated to the Department
of Energy and the National institute of Health
to initiate the HGP. The project officially began
in 1990 with a projected time frame of 15 years
to complete and an estimated cost of $3 billion
dollars. The goals of the HGP were as follows:
- Identify all human genes; while previous estimates
of the total number of genes ranged between 50,000
and 100,000, current estimates are closer to 30,000
genes.
- Determine the sequences of the 3 billion chemical
base pairs that make up human DNA, - Store this
information in databases,
- Improve tools for data analysis,
- Transfer related technology to the private sector,
and
- Address the ethical, legal and social issues
(ELSI) that may arise from the project.
From inception, the planners of the HGP aimed
for the data generated from the project to be
accessible and free. New data is released every
24 hours into GenBank, a database that serves
as a repository for sequence information. The
database is accessible at www.ncbi.nlm.nih.gov
and receives over 200,000 queries per day for
gene sequence information.
Due to advances in sequencing technology in both
the private and public sectors since the initiation
of the project, a working draft of the human genome
was completed in 2000. The draft contains gaps
and errors, but it provides a valuable template
for generating the complete genome sequence, which
is expected to be available by 2003 or earlier.
It is predicted that the availability of the completed
human genome sequence will advance the understanding
of how genetics influences disease development,
aid scientists looking for genes associated with
particular diseases, and contribute to the discovery
of new treatments.
To address the societal implications of the scientific
discoveries of the HGP, approximately 5% of the
annual budget is directed to the ELSI (ethical,
legal and societal implications) program. This
is the world’s largest bioethics program. The
ELSI program focuses on four main areas:
- the use and interpretation of genetic information
- clinical integration of genetic technology
- issues surrounding genetic research
- public and professional education about these
issues
One of the most active areas of the ELSI program
has been policy development related to the privacy
and fair use of genetic information, particularly
in health insurance, employment, and medical research.
Debates in this area focus largely on the potential
of genetic information to predict susceptibility
for disease in a currently healthy individual.
 Genetic
Counselling:
Genetic Counselling should be differentiated
from the larger field of clinical genetics due
to its intrinsic focus on communication and psychosocial
issues. Clinical genetic services focus on the
provision of diagnostic and prognostic services.
Although genetic counselling and clinical genetic
services are closely interwoven, and typically
offered together, the provision of genetic testing
may not encompass the genetic counselling process
in its entirety. Genetic counselling has been
defined by the American Society of Human Genetics
as: A communication process which deals with the
human problems as associated with occurrence,
or the risk of occurrence, of a genetic disorder
in a family. This process involves an attempt
by one or more appropriately trained persons to
help the individual or family to:
(1) Comprehend the medical facts, including the
diagnosis, probable cause of the disorder, and
the available management;
(2) Appreciate the way heredity contributes to
the disorder, and the risk of recurrence in specified
relatives;
(3) Understand the alternatives for dealing with
the risk of recurrence;
(4) Choose the course of action which seems to
them appropriate in view of their risk, their
family goals and their ethical and religious standards,
and to act in accordance with that decision; and
(5) Make the best possible adjustment to the
disorder in an affected family member and/or to
risk recurrence of that disorder(1).
Genetic counselling typically strives to facilitate
informed and autonomous decision-making, allowing
the client to make a decision in accordance with
their beliefs without passing judgment on the
worthiness of the life of a person affected with
a genetic condition(3). A non-directive approach
was incorporated as a basic tenet of genetic counselling
to underscore respect for the diverse values and
goals of those being counselled and to veer away
from eugenic connotations(2,10).
Traditionally the delivery of clinical genetic
services and genetic counselling is provided by
those with specialized training: clinical geneticists,
genetic counsellors and genetic nurses. In North
America there are over 1800 genetic counsellors,
who have trained in a two-year master’s level
program which offers course-work in basic science,
clinical genetics, risk assessment, behavioral
science, legal, ethical and ethoncultural issues,
as well as clinical and laboratory practice. This
training prepares genetic counsellors to comprehensively
address the unique needs of individuals/families
seeking genetic counselling. However, technological
advances together with the recognition of the
role of genetics in virtually every medical specialty
has necessitated the provision of genetic care
by primary care providers and clinical specialists,
e.g. oncologists, ophthal-mologists, cardiologists,
family physicians, etc.. Due to the limited number
of medical geneticists and genetic counsellors,
and the explosion of information generated by
the HGP. “Genetic Counselling” is currently being
provided by nongeneticists, a trend that will
certainly continue to expand. There exists a concern
that nongeneticist caregivers, are unprepared
for this role due to the inadequate amount of
genetics included in medical and nursing educational
curricula to date(7, 8, 10).
Genetic
Testing/Screening:
At this time molecular genetic tests can be used
to confirm a clinical diagnosis in a child/adult,
to screen for carriers of a number of autosomal
recessive disorders based on a positive family
history or ethnic background, and to provide prenatal
diagnostic information for those wishing such
information. Whereas genetic testing was once
sought most typically by couples with a family
history of early onset diseases (e.g. a child
with birth defects), for the purpose of family
planning, information about genetic status is
increasingly sought by persons who wish to learn
about their own predisposition to adult-onset
illness(4). Some anticipate that in the next decade,
as a result of the developments of the HGP, genetic
testing will no longer be utilized by a relatively
small proportion of the population but rather
that genomic medicine will be incorporated into
the provision of health care for all(8).
Genetic conditions with straightforward Mendelian
rules governing their inheritance and highly penetrant
single genes offer relatively straightforward
molecular testing interpretation. For some conditions
years of research have established the phenotypic
effect of a given mutation in a person and the
clinical course can be accurately predicted. However,
for many single gene disorders the detection of
a mutation does not predict the most likely clinical
course. Complicating factors, such as penetrance
and expressivity, prevent the mere knowledge of
the presence or absence of a given mutation from
predicting phenotype, clinical course or quality
of life for a person with a given genetic condition.
In fact these factors have posed dilemmas in the
provision of genetic counselling for single gene
disorders as the confirmation of a specific mutation
does not provide information on age onset (for
adult onset disorders) nor on severity in presentation-
even for mutations segregating within a family.
Some individuals seeking specific information
based on a molecular test result may experience
profound confusion, anger and/or depression when
presented with the limitations of clinical knowledge
associated with their test result even when counselled
prior to such testing. For many single gene disorders,
additional research is required to explain variations
in phenotype among mutation carriers and to correlate
genotype more closely with health outcomes.
While the field of clinical genetics continues
to struggle with the complicating factors of genetic
testing for single gene disorders, the discoveries
of the HGP launch an era of promise for the development
of new strategies for the diagnosis, prevention
and treatment of multifactorial diseases. However,
elucidating the genetic components of complex
disorders such as heart disease, autoimmune disorders,
diabetes, common cancers and psychiatric disorders,
which are believed to result from the interaction
of multiple genes at multiple loci, as well as
interactions with lifestyle and environmental
factors presents a formidable challenge. Currently
genetic testing in multifactorial or common genetic
disease remains of limited value.
Ethical
implications of the Human Genome Project:
In conjunction with the technological advances
of the HGP come inherent ethical challenges. Within
the field of clinical genetics it is accepted,
as part of the informed consent process, that
individuals pursuing genetic testing be provided
with a discussion of both the benefits and limitation
of genetic testing so that they understand the
potential implications of their test result(12).
However, despite the best intentions of health
care providers involved in clinical genetics,
it is impossible to anticipate all potential ethical
dilemmas arising from genetic testing. Below,
we present two clinical scenarios in an attempt
to encourage consideration of such challenges
in clinical practice.
Case
1:
Nazia and Abdul have four children; the eldest
three, aged 10, 8 and 6 years, are all in good
health. Nazia and Abdul were surprised when their
fourth child was identified with profound hearing
loss in the first year of life. Genetic testing
was undertaken in this child, Hassan, now aged
1.5 years, and revealed that he is homozygous
for a mutation in the GJB2 gene that alters the
protein connexin 26. Mutations in this gene account
for approximately 50% of autosomal recessive cases
of non-syndromic hearing loss(6). This testing
provided the family with the following information:
Nazia and Abdul would have a 25% risk of recurrence
for each subsequent pregnancy and their three
eldest children would each have a two-thirds chance
of carrying a mutation in one of their connexin
26 genes.
Case–related question: 1.
Should Nazia and Abdul be able to pursue genetic
testing for their three older children in order
to determine whether or not they are carriers?
Points to consider:
a. Being a carrier is not known to have any implication
on the hearing or health of these children. What
is the advantage of knowing their carrier status
at this time? Should the parents make this decision
for their children or should genetic testing be
deferred until the children are old enough to
take an active role in deciding to pursue this
information. The availability of DNA testing does
not automatically merit performing it.
b. Nazia and Abdul had hoped that their children
would marry Abdul’s brother’s children, and they
wonder if being identified as a carrier might
jeopardize this possibility. They also wonder
if this information may affect their childrens’
marriageability in their community at large. If
this testing were undertaken and the children
were to test as carriers, this could adversely
impact their sense of self (e.g. self esteem),
dependent upon their society’s view of the burden
of this condition.
Case
2:
Naser is 22 years of age and has just experienced
a massive myocardial infarction. Naser was at
home when this happened; he is employed as a bus
driver in Riyadh. On reviewing his family history,
the cardiologist learns that his father died shortly
after Naser’s birth of what Naser believes was
also a massive heart attack. The cardiologist
arranges for Naser to be tested for familial hypercholesterolemia
and this testing reveals that he is heterozygous
for a mutation in the LDL receptor gene. This
means that he inherited a mutation from one of
his parents, most likely his father given the
reported family history. In addition, each of
his brothers and sisters has a 50% risk for also
having inherited this mutation for familial hypercho-lesterolemia.
Hete-rozygotes have an elevated risk for coronary
artery disease, typically in the fourth or fifth
decade of life; homozygotes individuals who have
inherited a mutation from each of their parents,
characteristically have coronary heart disease
in childhood and may not survive beyond the third
decade (11). In addition, Naser has an identical
twin brother from whom he is estranged. This brother
is a transport truck driver who frequently carries
dangerous materials on busy urban roadways.
Case-related question:
1. Who should have access to Naser’s genetic
test result: his employer? His insurance carrier?
His brother?
Points to Consider:
a. Given that Naser has a significantly elevated
risk for a second myocardial infarct, should his
employer have access to his genetic test result?
If yes, is it justifiable to terminate Naser’s
employment with this company? If no, and Naser
has a heart attack while driving a bus filled
with passengers, is the company liable?
b. Should Naser’s insurance carrier disallow
his claim for medical coverage citing that his
heart disease was based on a pre-existing genetic
condition given his DNA test results?
c. If Naser refuses to share his genetic testing
results with his estranged brother, should the
cardiologist breach his confidentiality? Should
this decision be impacted by Naser’s brother’s
line of work and/or the level of his risk for
myocardial infarction as an obligate heterozygote?
While the discoveries of the HGP raise many challenging
ethical issues, there is also the promise of huge
advances in the diagnosis and treatment of genetic
conditions(4, 5). Although the clinical implications
of the HGP are still indeterminate due to the
complexities of the genome yet to be understood,
advances in pharmacogenetic treatments are becoming
a viable reality. It has been established already
that there are vast differences in the efficacy
and potential adverse effects of a given medication
from one person to the next. Analysis of a person’s
genetic makeup is likely, in the future, to allow
for individualized drug treatment regimes. Genetic
analysis may also allow for anticipatory medical
guidance; for example, encouraging an individual,
in conjunction with a health care provider’s supervision,
to actively alter his or her lifestyle with the
hope of potentially preventing or delaying the
onset of symptoms for common genetic disorders
such as diabetes. Both academic and commercial
laboratories will likely utilize microarray technology
to provide simultaneous genetic testing for a
large number of genetic disorders as such tests
are developed and validated(8). Consideration
regarding the provision of pretest counselling
for individuals pursuing such testing must be
given and efficient and effective protocols developed.
In addition, advances from the HGP will support
continued research on gene therapy hopefully leading
to successful treatment of genetic diseases. For
the goals of the HGP to be realized in the clinical
arena, however, safeguards to protect against
the misuse of genetic information will need to
be firmly in place(5). Essential steps for this
to occur must involve societal recognition of
these issues and the involvement of individuals
from a wide variety of backgrounds, including
science, law, ethics, religion, business and the
lay public in policy making. This is already occurring
in a number of countries around the world.
Another critical challenge must be met: physicians,
nurses, and other health care providers will need
to become familiar with the emerging field of
genetic medicine. The need for medical genetic
specialists (geneticists, genetic counsellors
and genetic nurse specialists) will remain considerable,
but the need will overcome the personnel and genetic
medicine will be practiced for the most part,
by primary care providers. Indeed, primary care
providers are typically most knowledgeable about
family dynamics and other personal issues thereby
allowing them to more easily anticipate potential
problems that may arise. In addition, public education
will be essential in order to demystify genetics
and empower individuals and their families to
make their own informed decisions regarding genetic
testing. The era of the HGP is upon us. It is
now society’s responsibility to determine how
this information and technology should be best
used.
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